Unique Statistics:

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Abstract

Objective :

Compare age-adjusted rates of death due to liver, kidney, and heart diseases during 2009-2011 among US residents diagnosed with HIV infection with those in the general population.

Methods :

Numerators were numbers of records of multiple-cause mortality data from the national vital statistics system with an ICD-10 code for the disease of interest (any mention, not necessarily the underlying cause), divided into those 1) with and 2) without an additional code for HIV infection. Denominators were 1) estimates of persons living with diagnosed HIV infection from national HIV surveillance system data and 2) general population estimates from the US Census Bureau. We compared age-adjusted rates overall (unstratified by sex, race/ethnicity, or region of residence) and stratified by demographic group.

INTRODUCTION

Due to highly active antiretroviral therapy (HAART), individuals with human immunodeficiency virus (HIV) infection are living longer1, are less likely to develop acquired immunodeficiency syndrome (AIDS) [1,2], and are more likely to die from a non-AIDS related cause [1-8]. Consequently, major causes of death (e.g., heart disease, kidney disease, and liver disease) that are not clearly attributable to HIV infection have acquired greater importance in the clinical management of HIV-infected persons. Previous analyses of multiple-cause data from death certificates found that liver, kidney, and heart diseases had become the third, fourth, and fifth most common causes of death, respectively, among HIV-infected individuals by 1999, after pneumonia and septicemia [9]. The percentage of deaths due to these three diseases increased during 1996- 2006 [10]. The risk of some types of heart disease and kidney disease may also be greater among HIV-infected persons than in the general population [11, 12]. Because of this relationship, the Health Resources and Services Administration’s Guide for HIV/AIDS Clinical Care recommends physicians to work closely with HIV-infected patients to reduce the risks of heart [13] and renal diseases [14]. Previous research investigating rates of death due to chronic disease in individuals diagnosed with HIV were conducted in Spain [2, 15], and France [16], but did not compare rates between individuals diagnosed with HIV and the general population [9, 10]. To our knowledge, this is the first study to compare rates of death due to kidney disease, specific types of heart disease (ischemic heart disease, heart failure, and cardiomyopathy) and liver disease (hepatitis B, hepatitis C, and other liver diseases) among individuals diagnosed with HIV infection with the corresponding rates in the general US population using data from all 50 states and the District of Columbia. This study controlled for age, sex, race/ethnicity, and region of residence. The study period was 2009-2011, which provided almost 2 million person-years of follow-up. This analysis was not limited to underlying causes of death because such a limitation might conceal a cause of interest among deaths for which the underlying cause was HIV infection.

Our comparison of death rates could be biased by under-reporting of heart, liver, or kidney disease on death certificates that report HIV infection. To look for evidence suggesting this, we also measured the percentage of death certificates in which HIV infection was the only cause reported (except for cardiac arrest or respiratory arrest) among death certificates with any mention of HIV infection. These would represent instances of under-reporting of other causes if it is assumed that HIV infection can cause death only through other diseases due to the HIV infection.

METHODS

Linkage of multiple-cause death-certificate data to persons reported to the national HIV surveillance system is incomplete at the individual level. To calculate cause-specific national death rates for individuals diagnosed with HIV infection, therefore, we used an “ecologic” method, defining numerators and denominators at only aggregate, demographic-group levels. We chose 2009 as the beginning of the study period because it followed the first year (2008) in which all 50 states and the District of Columbia had implemented confidential name-based reporting of HIV infection. Earlier then, health departments in some jurisdictions did not collect data on non-AIDS cases of HIV infection or accepted codes in places of names (which made removal of duplicate reports more difficult).

Numerators

To determine the number of deaths caused by HIV, we used the multiple-cause mortality data compiled by the National Center for Health Statistics (NCHS) through the National Vital Statistics System (NVSS). Mortality data from the NVSS included demographic, geographic, and cause-of-death information on all deaths among US residents that occurred in the United States. As a surrogate for the cause-specific number of deaths in the HIV-infected US population, we used the number of death certificates that mentioned both HIV infection and one or more of the other causes of death of interest--kidney disease, ischemic heart disease, heart failure, cardiomyopathy, hepatitis B, hepatitis C or other liver disease (excluding hepatitis B and C), regardless of which cause of death was designated the underlying cause. These would be underestimates to the extent that they omitted deaths of HIV-infected persons whose death certificates did not mention HIV infection. Conversely, as a surrogate for the numbers of deaths in the population without HIV infection (approximated by the general population), we used all death certificates that mentioned the diseases of interest but did not mention HIV infection. These would be overestimates to the extent that they included deaths of HIV-infected persons whose death certificates did not mention HIV infection. We selected the subcategories for liver disease (hepatitis B, hepatitis C, and liver disease excluding hepatitis B and C) based on previously published research associating HIV infection with these diseases [12,17-22]; subcategories for heart disease (ischemic heart disease, heart failure, cardiomyopathy) were also selected based on previous research [23-26].

HIV infection was identified by an International Classification of Diseases (ICD-10) code in the range B20.0—B24 or R75; liver disease was identified by an ICD-10 code in the ranges B15.0—B19.9 (viral hepatitis), C22.0 (primary liver cancer), and K70.0—K76.9 (other liver diseases); hepatitis B was identified by ICD-10 codes B16.0—B16.9, B17.0, B18.0, and B18.1; hepatitis C was identified by ICD-10 codes B17.1 and B18.2 Kidney disease was identified by an ICD-10 code in the range N00.0—N28.9 Ischemic heart disease was identified by an ICD-10 code in the range I20-I25; cardiomyopathy was identified by an ICD-10 code of I50; and heart failure was identified by an ICD-10 code of I42. Decedents reported with more than one of the diseases of interest were counted more than once (in an independent analysis for each disease).

Denominators

As a surrogate for the HIV-infected US population, we used the estimated numbers of persons diagnosed with HIV infection who were alive during 2009-2011, based on cases reported to the national HIV surveillance system as of December 31, 2012. In addition to allowing a lag of at least 12 months (between December 2011 and December 2012) for delays in reports of diagnoses and deaths, our estimates were weighted to adjust for reporting delays. The population of poeple diagnosed with HIV infection who were at risk of death in each year, 2009, 2010 and 2011, was estimated as the number of persons living with HIV infection at the beginning of each of these years (i.e., those diagnosed in previous years minus those who had died), plus the number of patients who were diagnosed and died in the same year, all adjusted for reporting delays [27]. Mid-year estimates of the general US population (surrogate for the population without HIV infection) in 2009, 2010, and 2011 were obtained from the US Bureau of the Census [28, 29]. Our use of the general population as a denominator slightly over-estimates the population not infected with HIV infection, because it includes HIV-infected persons.

Rates

For each of the causes of death, we calculated the rate of death with any mention of that cause on the death certificate in the population diagnosed with HIV infection and in the general population. The rate was age-adjusted using the 2000 projected US Population [30]. To calculate average annual rates over the entire study period (2009-2011), the numerators were the sum of deaths in the 3-year period and the denominators were the multi-year sums of the populations for each year (2009-2011) (person-years at risk). We divided the age-adjusted rate in the population diagnosed with HIV infection by the age-adjusted rate in the general population to calculate the ratio of age-adjusted rates (rate ratio) and its 95% confidence interval.

To calculate the percentage of deaths in which HIV infection was the only cause (except for cardiac or respiratory arrest) reported among death certificates with any mention of HIV infection, we linked a value of zero to ICD codes for HIV infection, cardiac arrest, and respiratory arrest, and linked a value of one (1) to every other ICD code. Then we summed those linked values for each death, and identified deaths comprising the numerator of the percentage as those for which this sum was zero.

RESULTS

Most individuals diagnosed with HIV infection who died during the study period were male, black/African American (hereafter referred to as black), and lived in the South. The same was true for the individuals not diagnosed with HIV infection who died in the study period (Table 1).

Table 1..

Rates of death with any mention of hepatitis Ba, hepatitis Cb, and other liver diseasec excluding hepatitis B or hepatitis C,
among persons diagnosed with HIV infectiond and the general population, by demographic characteristics, United States,
2009-2011.

Rates of Death with Hepatitis Ba

Diagnosed with HIV Infectiond

General Population

Rate Ratiof

95% CI

Deaths

Person-Years at Risk

Age-Adjusted Ratee

Deaths

Person-Years at Risk

Age-Adjusted Ratee

Sex at Birthg

Female

97

648,195

13.0

1,346

471,499,051

0.2

52.2

(24.6-79.8)

Male

571

1,935,792

23.0

3,653

456,194,614

0.8

30.6

(24.4-36.9)

Race/Ethnicity

Hispanic/Latino

74

488,058

16.3

418

152,163,251

0.4

36.6

(13.1-60.2)

Black/African American

293

1,128,187

19.9

919

118,597,589

0.8

24.1

(18.0-30.1)

White

287

874,839

24.7

2,410

600,612,647

0.3

78.3

(54.1-102.4)

Other

14

92,913

17.4

1,252

56,320,178

2.5

7.0

(0.5-13.5)

Region of Residence

Midwest

75

299,821

14.2

670

200,883,730

0.3

48.6

(36.0-61.2)

Northeast

176

697,195

18.9

878

166,020,807

0.5

41.7

(28.8-54.6)

South

271

1,095,263

20.1

1,775

344,452,880

0.5

42.7

(31.1-54.4)

West

146

491,721

28.3

1,676

216,336,248

0.7

38.2

(18.2-58.2)

Overallh

668

2,584,001

20.8

4,999

927,693,665

0.5

42.6

(34.6-50.7)

Rates of death with hepatitis Cc

Sex at birthg

Female

715

648,195

79.1

14,338

471,499,051

2.6

30.3

(26.6-33.9)

Male

2330

1,935,792

93.1

34,900

456,194,614

6.8

13.7

(12.6-14.8)

Race/Ethnicity

Hispanic/Latino

534

488,058

95.3

7,040

152163251

6.9

13.7

(11.0-16.5)

Black/African American

1,379

1,128,187

106.9

8,472

118,597,589

7.3

14.6

(13.0-16.1)

White

1,084

874,839

73.4

31,787

600,612,647

4.1

18.0

(16.5-19.5)

Other

48

92,913

51.6

1,939

56,320,178

3.9

13.1

(6.9-19.4)

Region of Residence

Midwest

251

299,821

64.7

7,319

200,883,730

3.1

20.9

(16.8-25.0)

Northeast

1046

697,195

101.4

7,301

166,020,807

3.6

27.8

(24.6-31.1)

South

1181

1,095,263

88.5

18,256

344,452,880

4.7

18.9

(16.9-21.0)

West

567

491,721

85.5

16,362

216,336,248

6.9

12.4

(10.4-14.4)

Overallh

3,045

2,584,001

89.9

49,238

927,693,665

4.6

19.4

(18.1-20.8)

Rates of death with liver disease excluding hepatitis Bb or hepatitis Cc

Sex at Birthg

Female

276

648,195

30.3

85,186

471,499,051

15.7

1.9

(1.6-2.2)

Male

1,166

1,935,792

50.5

140,390

456,194,614

29.6

1.7

(1.5-1.9)

Race/Ethnicity

Hispanic/Latino

253

488,058

48.7

27,352

152,163,251

29.6

1.6

(1.1-2.2)

Black/African American

571

1,128,187

39.3

22,700

118,597,589

21.0

1.9

(1.6-2.1)

White

574

874,839

51.1

166,094

600,612,647

21.8

2.3

(1.9-2.8)

Other

44

92,913

36.1

9,430

56,320,178

19.1

1.9

(1.0-2.8)

Region of Residence

Midwest

153

299,821

37.5

46,010

200,883,730

20.5

1.8

(1.4-2.3)

Northeast

330

697,195

36.0

37,377

166,020,807

19.4

1.9

(1.4-2.3)

South

673

1,095,263

48.7

87,053

344,452,880

23.2

2.1

(1.8-2.4)

West

286

491,721

55.6

55,136

216,336,248

24.7

2.3

(1.6-2.9)

Overallh

1,442

2,584,001

45.6

225,576

927,693,665

22.2

2.1

(1.8-2.3)

aIdentified by an ICD-10 code of B16.0-B16.9, B17.0, B18.0, or 18.1; bIdentified by an ICD-10 code of B17.1 or B18.2; cIdentified by an ICD-10 in the range of B15.0-B18.9, or
C22.0, or K70.0-K76.9, but excluding B16.0-B16.9, B17.0, B17.1, and B18.0-B18.2; dIdentified by an ICD-10 code in the range B20.0-B24 or R75; eDeaths per 100,000 personyears,
adjusted for age using the 2000 projected US population; fRatio of age-adjusted rates comparing persons diagnosed with HIV infection to those in the general population; gTen
person years were excluded from the sex at birth analysis because the individuals who contributed those person-years at risk were missing information on sex at birth; hSubpopulation
totals may not equal overall total due to rounding and exclusions; overall total includes 10 person-years contributed by individuals missing information on sex at birth.

Table 2..

Rates of death with any mention of kidney diseasea among persons diagnosed with HIV infectionb and the general
population, by demographic characteristics, United States, 2009-2011.

Diagnosed with HIV Infectionb

General Population

Rate
Ratiod

95%
CI

Deaths

Person-Years at Risk

Age-Adjusted Ratec

Deaths

Person-Years at Risk

Age-Adjusted Ratec

Sex at Birthe

Female

1,238

648,195

232.3

381,065

471,499,051

65.5

3.5

(3.1-4.0)

Male

3,176

1,935,792

177.7

407,734

456,194,614

98.8

1.8

(1.6-2.0)

Race/Ethnicity

Hispanic/Latino

463

488,058

106.8

56,081

152,163,251

76.0

1.4

(1.1-1.7)

Black/African American

3,006

1,128,187

283.9

124,113

118,597,589

138.8

2.0

(1.9-2.2)

White

900

874,839

127.3

581,859

600,612,647

72.8

1.7

(1.5-2.0)

Other

45

92,913

95.7

26,746

56,320,178

66.5

1.4

(0.5-2.4)

Region of Residence

Midwest

462

299,821

213.8

188,353

200,883,730

83.0

2.6

(1.8- 3.3)

Northeast

1,008

697,195

149.7

140,353

166,020,807

70.6

2.1

(1.8- 2.4)

South

2,381

1,095,263

243.0

297,610

344,452,880

82.8

2.9

(2.7- 3.2)

West

563

491,721

134.0

162,483

216,336,248

76.5

1.8

(1.3- 2.2)

Overallf

4,414

2,584,001

190.3

788,799

927,693,665

79.2

2.4

(2.2- 2.6)

aIdentified by an ICD-10 code in the range N00.0-N28.9; bIdentified by an ICD-10 code in the ranges B20.0-B24 or R75; cDeaths per 100,000 person-years, adjusted for age using
the 2000 projected US population; dRatio of age-adjusted rates comparing persons diagnosed with HIV infection to those in the general population; eEight person-years were
excluded from the sex at birth analysis because the individuals who contributed those person-years at risk were missing information on sex at birth; fSubpopulation totals may not
equal overall total due to rounding and exclusions; overall total includes 8 person-years contributed by individuals missing information on sex at birth.

Table 3..

Rates of death with any mention of ischemic heart diseasea, heart failureb, and cardiomyopathyc among persons
diagnosed with HIV infectiond and the general population, by demographic characteristics, United States, 2009-2011.

Rates of Death with Ischemic Heart Diseasea

Diagnosed with HIV Infectionb

General Population

Rate Ratiof

95% CI

Deaths

Person-Years at Risk

Age-Adjusted Ratee

Deaths

Person-Years at Risk

Age-Adjusted Ratee

Sex at Birthg

Female

296

648,195

80.4

731,452

471,499,051

123.1

0.7

(0.5-0.8)

Male

1,367

1,935,792

108.6

904,689

456,194,614

216.3

0.5

(0.4-0.6)

Race/Ethnicity

Hispanic/Latino

194

488,058

96.5

86,693

152,163,251

124.9

0.8

(0.5-1.0)

Black/African American

732

1,128,187

97.4

162,861

118,597,589

184.3

0.5

(0.4-0.6)

White

720

874,839

117.0

1,345,925

600,612,647

167.5

0.6

(0.5-0.7)

Other

17

92,913

31.5

40,662

56,320,178

102.0

1.0

(0.8-1.2)

Region of Residence

Midwest

203

299,821

98.7

386,514

200,883,730

169.4

0.6

(0.4-0.8)

Northeast

360

697,195

81.3

343,881

166,020,807

171.2

0.5

(0.4-0.6)

South

797

1,095,263

111.6

594,918

344,452,880

165.1

0.7

(0.6-0.8)

West

303

491,721

120.5

310,828

216,336,248

146.0

0.8

(0.6-1.1)

Overallh

1,663

2,584,001

102.5

1,636,141

927,693,665

163.5

0.6

(0.6-0.7)

Rates of Death with Heart Failureb

Sex at Birthg

Female

317

648,195

87.7

467,332

471,499,051

77.2

1.1

(0.8-1.1)

Male

673

1,935,792

57.0

386,949

456,194,614

97.3

0.6

(0.5-0.7)

Race/Ethnicity

Hispanic/Latino

106

488,058

56.4

36,278

152,163,251

55.3

1.0

(0.6-1.4)

Black/African American

602

1,128,187

65.9

79,164

118,597,589

92.9

0.7

(0.6-0.8)

White

270

874,839

70.4

721,827

600,612,647

88.5

0.8

(0.6-1.0)

Other

12

92,913

34.0

17,012

56,320,178

45.3

0.7

(0.0-1.7)

Region of Residence

Midwest

104

299,821

115.5

213,110

200,883,730

92.6

1.2

(0.6-1.9)

Northeast

219

697,195

55.6

158,546

166,020,807

77.7

0.7

(0.5-0.9)

South

497

1,095,263

57.9

308,032

344,452,880

86.9

0.7

(0.5-0.8)

West

170

491,721

74.4

174,593

216,336,248

83.1

0.9

(0.6-1.2)

Overallh

990

2584001

64.9

854,281

927,693,665

85.7

0.8

(0.6-0.9)

Rates of Death with Cardiomyopathyc

Sex at Birthg

Female

130

648,195

31.4

56,849

471,499,051

9.9

3.2

(1.8-4.6)

Male

441

1,935,792

26.3

84,824

456,194,614

20.0

1.3

(1.0-1.6)

Race/Ethnicity

Hispanic/Latino

43

488,058

17.3

8,579

152,163,251

10.8

1.6

(0.3-2.9)

Black/African American

368

1,128,187

33.4

22,625

118,597,589

23.8

1.4

(1.1-1.7)

White

149

874,839

25.9

106,890

600,612,647

13.7

1.9

(1.2-2.6)

Other

11

92,913

11.0

3,579

56,320,178

8.3

1.3

(0.4-2.2)

Region of Residence

Midwest

70

299,821

25.3

32,284

200,883,730

14.4

1.8

(1.0-2.5)

Northeast

89

697,195

20.8

25,612

166,020,807

13.1

1.6

(0.8-2.3)

South

309

1,095,263

34.3

55,142

344,452,880

15.4

2.2

(1.6-2.9)

West

103

491,721

21.6

28,635

216,336,248

13.4

1.6

(1.1-2.1)

Overallh

571

2,584,001

27.7

141,673

927,693,665

14.3

1.9

(1.6-2.3)

aIdentified by an ICD-10 code in the ranges I20-I25; bIdentified by an ICD-10 code in the ranges I50; cIdentified by an ICD-10 code in the ranges I42; dIdentified by an ICD-10 code
in the ranges B20.0-B24 or R75; eDeaths per 100,000 person-years, adjusted for age using the 2000 projected US population; fRatio of age-adjusted rates comparing persons
diagnosed with HIV infection to those in the general population; gEight person-years were excluded from the sex at birth analysis because the individuals who contributed those
person-years at risk were missing information on sex at birth; hSubpopulation totals may not equal overall total due to rounding and exclusions; overall total includes 8 person-years
contributed by individuals missing information on sex at birth.

Death Due to Hepatitis B

Overall, individuals with diagnosed HIV infection had rates of death due to hepatitis B that were 43 times that of the general population (Table 1). For each sex, persons diagnosed with HIV infection had a higher rate of death due to hepatitis B than their counterparts in the general population. Among women the rate ratio (RR) was 52.2, with a 95% confidence interval (CI) of 24.6-79.8; among men the RR was 30.6 (95% CI: 24.4-36.9) (Table 1). In every racial/ethnic group, individuals diagnosed with HIV infection had higher rates of death due to hepatitis B than those of the same racial/ethnic group in the general population (Table 1). Among racial/ethnic groups, whites had the highest rate (RR=78.3; 95% CI: 54.1-102.4), with Hispanics/Latinos second (RR=36.6; 95%CI: 13.1-60.2), followed by blacks (RR=24.1; 95%CI: 18.0-30.1) (Table 1). In every region of residence, persons with diagnosed HIV infection had higher rates compared to the general population with the highest rates occurring in the Midwest (RR=48.6; 95% CI: 36.0-61.2) (Table 1).

Deaths Due to Hepatitis C

Both women (RR=30.3; 95% CI: 26.6-33.9) and men (RR=13.7; 95% CI: 12.6-14.8) with diagnosed HIV infection had significantly higher rates of death due to hepatitis C than their counterparts in the general population (Table 1). The same was true for every racial/ethnic group, with whites diagnosed with HIV infection having the largest differences in rates of death due to hepatitis C compared to whites in the general population (RR=18.0; 95% CI: 16.5-19.5) (Table 1). In every region of residence, persons with diagnosed HIV infection had higher rates compared to the general population with the highest rates in the Northeast (RR=27.8; 95% CI: 24.6-31.1) (Table 1).

Death Due to Liver Disease Excluding Hepatitis B or C

For each sex, persons diagnosed with HIV infection had significantly higher rates of death due to liver disease excluding hepatitis B or C than their counterparts in the general population (among women the rate ratio [RR] was 1.9, with a 95% confidence interval [CI] of 1.6-2.2; among men the RR was 1.7 (95% CI: 1.5-1.9) (Table 1). In almost every racial/ethnic group, persons diagnosed with HIV infection had significantly higher rates of death due to liver disease excluding hepatitis B or C than those of the same racial/ethnic group in the general population. Among racial/ethnic groups, the RR ranged from 1.6 ; 95% CI: 1.1-2.2 for Hispanics/Latinos) to 2.3 (95% CI: 1.9-2.8 for whites). Only individuals in the other race/ethnicity category did not have a significantly higher rate of death than the general population. In every region of residence, persons with diagnosed HIV infection had higher rates compared to the general population, with the RR ranging from 1.8 (95% CI: 1.4-2.3) in the Midwest to 2.3 (95% CI: 1.6-2.9) in the West (Table 1).

A strong association between HIV infection and hepatitis B and C was also shown simply by the overlapping distribution of causes of deaths (without calculating death rates). The percentage of deaths reported with HIV infection was much higher among deaths reported with hepatitis B (10.5%), hepatitis C (5.3%), or both (14.8%), than among those reported with only other liver diseases (0.6%) (p<0.0001, chi-square test). Conversely, the percentage of deaths reported with hepatitis B or C among deaths reported with HIV infection was more than ten times that among deaths not reported with HIV infection. Among all 29,614 deaths in 2009-2011 reported with HIV infection, 384 (1.30%) were reported with hepatitis B but not C; 2,768 (9.35%) with hepatitis C but not B, and 243 (0.82%) with both. In contrast, among the 7,422,714 deaths in the same period not reported with HIV infection, 3,660 (0.05%) were reported with hepatitis B but not C; 48,219 (0.65%) with hepatitis C but not B; and 1,445 (0.02%) with both.

Deaths Due to Kidney Disease

Females (RR=3.5; 95% CI: 3.1-4.0) and males (RR=1.8; 95% CI: 1.6-2.0) diagnosed with HIV infection had significantly higher rates of death with any mention of kidney disease compared to their counterparts in the general population (Table 2). In almost every racial/ethnic group, persons diagnosed with HIV infection had significantly higher rates of death with any mention of kidney disease than those of the same racial/ethnic group in the general population. Among race/ethnicities, blacks with HIV infection had the largest difference in rate of death with any mention of kidney disease when compared with their counterpart in the general population (RR=2.0; 95% CI: 1.9-2.2) (Table 2). In every region of residence at death, persons diagnosed with HIV infection had significantly higher rates of death with any mention of kidney disease compared to the general population, with the highest rate ratio being among individuals residing in the South (RR=2.9; 95% CI=2.2-3.6) (Table 2).

Deaths Due to Ischemic Heart Disease

Unlike the previous findings with certain types of liver disease and with kidney disease, females (RR=0.7; 95% CI: 0.5-0.8) and males (RR=0.5; 95% CI=0.4-0.6) diagnosed with HIV infection had significantly lower rates of death due to ischemic heart disease compared to their counterparts in the general population (Table 3). The findings were similar among almost all racial/ethnic groups (except Hispanics/ Latinos) and in every region of residence (Table 3).

Deaths Due to Heart Failure

Males diagnosed with HIV infection had a significantly lower rate of death due to heart failure than their counterparts in the general population (RR=0.6; 95% CI: 0.5-0.7). The same was true for blacks (RR=0.7; 95% CI: 0.6-0.8) and individuals who resided in the Northeast (RR=0.7; 95% CI: 0.5-0.9) and in the South (RR=0.7; 95% CI: 0.5-0.8).

Deaths Due to Cardiomyopathy

Females (RR=3.2; 95% CI: 1.8-4.6) diagnosed with HIV infection had significantly higher rates of death due to cardiomyopathy than their counterparts in the general population (Table 3). Similar results were observed for blacks (RR=1.4; 95% CI: 1.1-1.7), whites (RR=1.9; 95% CI: 1.2-2.6), and individuals who resided in the South (RR=2.2; 95% CI: 1.6-2.9) and the West (RR=1.6; 95% CI: 1.1-2.1).

Deaths Due to HIV Infection

During 2009‒2011, of the 25,141 death certificates that mentioned HIV as a cause, 3,891 (15.5%) had no other cause mentioned (not counting cardiac or respiratory arrest). Of those death certificates that mentioned HIV infection, 2,715, also mentioned viral hepatitis; 1,058, other liver disease (without hepatitis); 3,611, kidney disease; and 3,316, heart disease. In those four subgroups, HIV infection was selected as the underlying cause in 75.5%, 69.6%, 83.8%, and 63.7%, respectively.

DISCUSSION

This analysis is unique because it was based on reporting of HIV infection diagnoses and causes of death for the population of the entire nation (all 50 states and the District of Columbia). The large number of observations and all the person years of follow-up argue in favor of the validity of our findings.

We found that HIV-infected persons have significantly higher rates of death due hepatitis B, hepatitis C, and liver disease excluding hepatitis B or C, when compared to the general population. These findings are consistent with the results of previous research [12]. The higher rates may not necessarily be due to HIV infection itself, but could be due to common risk factors for both HIV infection and the liver diseases, such as shared modes of transmission of HIV and viral hepatitis [17-19], or high-risk life styles that expose persons to multiple diseases. Thus, the higher rates of death with both types of hepatitis among persons diagnosed with HIV infection than in the general population could have been due to higher prevalence of hepatitis among HIV-infected persons. If we had been able to control for the prevalence of hepatitis among the two populations by limiting the death rate denominators to persons with hepatitis, we might have found no differences between their rates of death with hepatitis.

Our finding that rates of death with hepatitis C were higher than rates of death with hepatitis B among both persons diagnosed with HIV infection and the general population is consistent with hepatitis C being more prevalent than hepatitis B in both populations. The fact that the rate ratio comparing the death rate among persons diagnosed with HIV infection with that in the general population was higher for hepatitis B than for hepatitis C is due to the rates of death in the two populations being more similar for hepatitis C than for hepatitis B. This, in turn, may be explained by the prevalence of hepatitis C in the general population being more similar to that among persons diagnosed with HIV infection.

Individuals diagnosed with HIV infection had significantly higher rates of death due to kidney disease than their counterparts in the general population for every sexual and racial/ethnic group, and region of residence. These findings are consistent with previous studies that found that kidney disease is more common in HIV-infected individuals [31]. One possible explanation for the increased risk of death due to kidney disease among individuals diagnosed with HIV infection may be HIV-associated nephropathy, some of which may be due to nephrotoxicity of antiretroviral drugs rather than to HIV alone [32, 33].

We also found that females, males, persons in most racial/ethnic groups, and individuals residing in most regions of the country who were diagnosed with HIV infection had significantly lower rates of death due to ischemic heart disease than the general population. This seems to contradict the association of HIV infection with ischemic heart disease found by other studies, such as the finding that highly active antiretroviral therapy was associated with an increase in intima media thickness of the carotid artery [23]. However, previous studies have produced conflicting results regarding whether individuals with HIV infection are more susceptible to ischemic heart disease [34-39].

Males, blacks, and individuals residing in the Northeast or South who were diagnosed with HIV infection had significantly lower rates of heart failure when compared to their counterparts in the general population. The lower rates were found despite age adjustment, and thus are not explained by HIV-infected persons dying younger than the general population. These findings contradict previous studies that found that individuals with HIV infection had an increased risk of death due to heart failure [24, 25]. Other investigators have attributed the increased risk that they found to factors such as increased atherosclerosis due to inflammation [40] or endothelial dysfunction to HIV replication [41, 42].

Females, blacks, whites, and individuals who resided in the South or Midwest who were diagnosed with HIV infection had significantly higher rates of cardiomyopathy than the general population. These results are consistent with previous research which determined that individuals diagnosed with HIV infection had had an increased risk of dying with cardiomyopathy [26]. Previous research has attributed the increased risk of cardiomyopathy to HIV infection of the myocardium, HIV treatment toxicity, opportunistic infections, or nutritional deficiencies [43, 44].

In this analysis, we made full use of the multiple-cause mortality data by counting a disease as a cause of death if there was any mention of it on the death certificate, regardless of whether it was classified as the underlying cause, the immediate cause, an intermediate cause, or only a contributing cause. The alternative of limiting the analysis to underlying causes would have concealed most of the diseases of interest (liver, kidney or heart disease) whenever they and HIV infection were reported together, as HIV was selected as the underlying cause in most such deaths. As an infectious disease, viral hepatitis would have been even more likely to be concealed than the non-infectious diseases, because the ICD-10 rules for selecting the underlying cause state that “any infectious disease …should be considered… a direct consequence of reported HIV disease.” Consequently, even if viral hepatitis initially appeared to be the underlying cause, HIV infection would ultimately have been selected as the underlying cause if HIV infection were reported anywhere on the death certificate, “whether in Part I or Part II. [45]. Alternative approaches, such as review of medical records, laboratory reports, and autopsy results by an independent panel of physicians, have been suggested as ways to recognize the contribution of non-underlying causes to the deaths of persons dying of HIV infection, and possibly to correct errors made by certifiers [46], but these would have been impractical to apply to the large numbers of deaths in our analysis.

This study has some limitations. First, our data on deaths due to liver, kidney, or heart diseases were based on information from death certificates, which is subject to error, especially for deaths without autopsies [47]. Possibly reflective of this, 16% of the deaths in which HIV was mentioned as a cause had no other cause mentioned, which suggests that other causes, such as liver, kidney, or heart disease, may have been under-reported among deaths reported with HIV infection. Second, because all 50 states did not implement name-based HIV reporting until 2008, we did not think it would be worthwhile to investigate national trends in causes of death, as these would have been limited to the short period 2009--2011. However, limiting the study to 2009-2011 enabled us to include all 50 states and the District of Columbia, which made the data nationally representative of individuals diagnosed with HIV infection. This study did not control for some factors that could contribute to heart, liver, or kidney diseases (e.g., smoking, obesity, diabetes, hypertension, hypercholesterolemia). Finally, we did not link the death data with reported cases of HIV infection at the individual level, but instead estimated the number of deaths among persons diagnosed with HIV infection by depending on HIV infection being reported on death certificates. According to the instructions on death certificates, diseases or injuries should not be reported unless they caused or contributed to the death. Thus, if a person diagnosed with HIV infection died of a condition that the certifier thought was not attributable to or aggravated by HIV infection, and HIV infection did not contribute to the death in any other way, then the HIV infection should not have been reported on the death certificate. Consequently, we must have under-counted deaths among persons diagnosed with HIV infection, which reduced our chances of finding higher rates of death with other diseases (e.g., heart diseases) in this population, but we found some higher rates (e.g., with liver and kidney diseases) despite this limitation. Because death certificates were not linked to HIV case reports, we could not determine persons with unreported HIV infection. Therefore, we were unable to perform a sensitivity analysis.

Understanding the relationship between HIV infection and liver, kidney, and heart diseases will enable public health practitioners and physicians to intervene more effectively to address these illnesses and improve health outcomes for individuals diagnosed with HIV infection [11, 12, 19, 23, 48]. This becomes even more important as the percentage of older individuals increases among persons diagnosed with HIV infection. Our findings reemphasize the need for healthcare providers to consider these common diseases that seem unrelated to HIV infection when caring for patients with HIV infection. These findings also highlight the need to further explore the effect that chronic HIV infection and concurrent infection with liver, kidney, or heart disease has in the long term health of women.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

DISCLAIMER

The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention

World Health Organization.Rules and guidelines for mortality and morbidity coding. In International statistical classification of diseases and related health problems. Geneva World Health Organization 1993; 10(2): 39.

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